This invention relates to novel (substituted naphthalenyl)-3H-1,2,3,5-oxathiadiazole 2-oxides, to the processes for their preparation, to methods for using the compounds, and to pharmaceutical compositions thereof. The compounds have pharmaceutical properties which render them beneficial for the treatment of diabetes mellitus and associated conditions.
The serious complications of diabetes mellitus such as nephropathy retinopathy, neuropathy and cataract are all associated with an excessive amount of blood glucose. The major therapeutic objective is therefore the normalization of blood glucose, both in the fasting and postprandial situations.
The therapeutic approaches to the treatment of Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II) involve the use of diet, insulin or orally active hypoglycemic agents. Presently, such orally active hypoglycemic agents are chosen (a) from sulfonylureas such as chloropropamide, glyburide and others or (b) biguanides such as metformin and related products. Both these groups of agents have serious disadvantages. Sulfonylureas, upon chronic use, lose their effectiveness. In contrast, biguanides suffer from serious side effect, lacticacidosis.
More recently, oxazolidinedione (U.S. Pat. No. 4,342,771) and thiazolidinedione (European patent application No. 117,035) derivatives have been described as useful hypoglycemic agents. U.S. Pat. No. 4,461,902 discloses substituted 5-[(4-cyclohexyl-methoxyphenyl)methyl]thiazolidine-2,4-diones of formula ##STR1## wherein R is methyl (ciglitazone) and related analogues as hypoglycemic agents.
The compounds of the present invention are represented by formula (I) ##STR2## wherein R.sup.1 and R.sup.2 are independently hydrogen, lower alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, ethynyl, methylthio, nitro or halogen; Z is ##STR3## wherein R.sup.3 is hydrogen, lower alkyl containing 1 to 3 carbon atoms, alkoxy containing 1 to 2 carbon atoms, or benzyl; R.sup.4 is lower alkyl containing 1 to 3 carbon atoms, alkoxy containing 1 to 2 carbon atoms, or benzyl; n.sup.1 is 0, 1, or 2; n.sup.2 is 0, 1, or 2; or Z is --S--CH.sub.2 --, --SO.sub.2 --CH.sub.2 -- or --OCH.sub.2 --; or Z is --C(R.sup.5).dbd.C(R.sup.6)--, wherein R.sup.5 and R.sup.6 are independently hydrogen or lower alkyl containing 1 to 3 carbon atoms, and the pharmaceutically acceptable salts thereof.
Preferred compounds of the present invention are represented by formula (II) ##STR4## wherein R.sup.1 and R.sup.2 are independently hydrogen, lower alkyl containing 1 to 6 carbon atoms, or halogen; n.sup.1 and n.sup.2 are independently 0 or 1; R.sup.3 is hydrogen, lower alkyl containing 1 to 3 carbon atoms, alkoxy containing 1 to 2 carbon atoms; R.sup.4 is lower alkyl containing 1 to 3 carbon atoms or alkoxy containing 1 to 2 carbon atoms, and the pharmaceutically acceptable salts thereof.
The oxathiadiazole 2-oxide portion of the compounds of the present invention can exist in more than one tautomeric form. For clarity, only one of the tautomers is represented in the generic formulas (I) and (II) above. The possible tautomeric forms are listed below: ##STR5##
All of said tautomers are included in the present invention. The actual tautomeric form which the compounds of the present invention assume is not known.
This invention also includes mixtures of optically active isomers or partially or completely resolved isomers of the compounds disclosed.
The compounds of this invention are useful as antidiabetic agents for the reduction of blood/plasma sugar levels and for the treatment and/or prevention of diabetic complications and as antihyperlipidemic and antihyperinsulinemic agents.
The still further preferred compounds of the present invention are:
4-[1-(5-bromo-2-naphthalenyl)ethyl]-3H-1,2,3,5-oxathiadiazole 2-oxide; PA0 4-[1-(3-methyl-2-naphthalenyl)ethyl]-3H-1,2,3,5-oxathiadiazole 2-oxide; PA0 4-[1-methyl-2-(2-naphthalenyl)ethyl]-3H-1,2,3,5-oxathiadiazole 2-oxide; PA0 4-[1-(2-naphthalenyl)ethyl]-3H-1,2,3,5-oxathiadiazole 2-oxide; PA0 4-[(2-naphthalenyloxy)methyl]-3H-1,2,3,5-oxathiadiazole 2-oxides; PA0 4-[2-(2-naphthalenyl)ethyl]-3H-1,2,3,5-oxathiadiazole 2-oxide; PA0 4-[(2-naphthalenylthio)methyl]-3H-1,2,3,5-oxathiadiazole 2-oxide; PA0 4-[2-(2-naphthalenyl)propyl]-3H-1,2,3,5-oxathiadiazole 2-oxide; PA0 4-[1-methyl-1-(2-naphthalenyl)ethyl]-3H-1,2,3,5-oxathiadiazole 2-oxide; PA0 4-[1-(2-naphthalenyl)-2-phenylethyl]-3H-1,2,3,5-oxathiadiazole 2-oxide; PA0 4-[2-methoxy-2-(2-naphthalenyl)ethyl]-3H-1,2,3,5-oxathiadiazole 2oxide; PA0 4-[2-naphthalenylsulfonyl)methyl]-3H-1,2,3,5-oxathiadiazole 2-oxide;
and the pharmaceutically acceptable salts thereof.